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Neurobiol Dis. 2018 Nov;119:121-135. doi: 10.1016/j.nbd.2018.08.001. Epub 2018 Aug 6.

Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function.

Author information

1
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen 37073, Germany.
2
Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany.
3
Department for Functional Genomics, Center for Translational and Clinical Research, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia.
4
Institute of Medical Genetics and Applied Genomics, Faculty of Medicine, University of Tübingen, Tübingen 72076, Germany.
5
Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE) Göttingen, Göttingen, Germany; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
6
Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
7
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen 37073, Germany; CEDOC - Chronic Diseases Research Center, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisboa, Portugal; Max Planck Institute for Experimental Medicine, Göttingen 37075, Germany; Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle NE2 4HH, UK. Electronic address: touteir@gwdg.de.

Abstract

Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, COL4A2, a major component of basement membranes, was found to be upregulated in both A30P aSyn transgenic mice and in dopaminergic neurons expressing A30P aSyn, suggesting a crucial role for collagen related genes in aSyn-induced toxicity. Finally, we observed that A30P aSyn alters Golgi morphology and increases the susceptibility to endoplasmic reticulum (ER) stress in dopaminergic cells. In total, our findings provide novel insight into the putative role of aSyn on transcription and on the molecular mechanisms involved, thereby opening novel avenues for future therapeutic interventions in PD and other synucleinopathies.

KEYWORDS:

A30P alpha-synuclein; COL4A2; ER stress; Golgi fragmentation; Transcription deregulation

PMID:
30092270
DOI:
10.1016/j.nbd.2018.08.001

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